Pyrrolo(3,4-d)pyrimidinone derivatives and their use as...

Details Pyrrolo(3,4-d)pyrimidinone derivatives and their use as... Pyrrolo(3,4-d)pyrimidinone derivatives and their use as...

2000-02-17

2001-04-03

Berch, Mark L (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06211368

ABSTRACT:

The present invention provides certain novel 5-substituted pyrrolo[3,4-d]-pyrimidine-2,4-diones, processes for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and methods of treatment involving their use.
T-cells play an important role in the immune response, however in autoimmune disease T-cells are activated against particular tissues, e.g. causing the inflammation associated with rheumatoid arthritis. Interleukin-2 (IL-2) is an essential autocrine growth factor for T-cells and hence inhibition of IL-2 transcription is beneficial in the modulation of autoimmune disease. Formation of a transcriptional complex of the protein nuclear factor of activated T-cells-1 (NFAT-1) on the IL-2 promoter is essential for IL-2 transcription. NFAT-1 mediated transcription has therefore been proposed as appropriate molecular target for immunomodulation, Y. Baine et al.,
J. Immunol.,
1995, 154, 3667-3677.
W. F. Michne et al., in
J. Med. Chem
. (1995) 38, 2557-2569 disclose a number of quinazoline-2,4-diones and pyrrolo[3,4-d]pyrimidine-2,4-diones which inhibit transcription regulated by the DNA region bound by the NFAT-1 protein.
WO 96/17610 discloses the use of compounds of the following general formula and their salts as anti-ischaemic agents,
wherein R1, R2 and R3 which may be the same or different are N or CH; X1 and X2 which may be the same or different are hydrogen, hydroxy or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group and Z1 and Z2 which may be the same or different are hydrogen, hydroxy, keto or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group or one of Z1 and X1 and Z2 and X2 form the second bond of a double bond at the 1,6 or 2,3 positions, with the proviso that at least one of the groupings R1Z1X1, R2Z2X2 and R1X1Z2 form a hydroxamate moiety (—N(OH)C(═O)—) in which R1 and/or R2 is N, Z1 and/or Z2 is ═O and X1 and/or X2 is OH or R1 is N, Z2 is ═O and X1 is OH and B is a 5- or 6-membered ring of formula
in which R4, R5, R6, R7, R8, R9 and R10 which may be the same or different are CH or N with the proviso that ring B cannot contain more than 3 ring members which are nitrogen and the ring B may optionally be substituted by one or more of hydroxy, keto and an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group. Preferred compounds of WO 96/17610 include those compounds in which the ring B contains no substituent groups.
In accordance with the present invention, there is provided a compound according to the general formula:
wherein
W represents —CH
2
— or a bond; Q represents Ar
1
or Ar
2
; in the case where W represents —CH
2
—, Q represents an aryl group Ar
1
wherein Ar
1
represents naphthyl, phenyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl; in the case where W represents a bond, Q represents an aryl group Ar
2
wherein Ar
2
represents acenaphthenyl, fluorenyl or indanyl; wherein the ring systems which Ar
1
and Ar
2
represent may all be optionally substituted by one or more substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halogen, or trifluoromethyl; R
10
represents X—(A)
p
—Y; X represents S(O)
n
, C≡C, (CH
2
)
2
, CH═CH or CH
2
CH═CH; n represents 0, 1 or 2; A represents C
1-6
alkylene; p is 0 or 1; Y represents CN, OR
11
, CO
2
R
12
, CONR
13
R
14
, NR
15
R
16
, NHSO
2
R
17
, NHCOR
18
or an optionally substituted aryl or heteroaryl group, provided that when X represents S(O)
n
and Y is other than an optionally substituted aryl or heteroaryl group, then p is 1 and also provided that when X represents S(O)
n
, p is 1 and Y represents OH, then n is not 0; R
13
and R
14
independently represent H, C
1-5
alkyl or phenyl, which latter group may be substituted by one or more substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halogen, or CO
2
R
21
; and R
1
, R
2
, R
11
, R
12
, R
15
, R
16
, R
17
, R
18
and R
21
independently represent H or C
1-5
alkyl; or a pharmaceutically acceptable derivative thereof.
In the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in an alkoxy, alkoxycarbonyl, alkylsulphonamido, (di)alkylamido, (di)alkylamino or acylamino substituent group may be linear or branched.
When W in formula (I) represents —CH
2
—, then Q represents an aryl group Ar
1
wherein Ar
1
preferably represents a naphthyl or phenyl group, especially a naphthyl group, which aryl group may be optionally substituted by one or more, preferably one to four, particularly one or two, substituents selected from C
1-4
alkyl, e.g., methyl or ethyl, C
1-4
alkoxy, e.g. methoxy or ethoxy, halogen, e.g. fluorine, chlorine or bromine, or trifluoromethyl. Ar
1
is preferably an unsubstituted naphthyl group.
When W in formula (I) represents a bond, then Q represents an aryl group Ar
2
wherein Ar
2
preferably represents an indanyl group, which may be optionally substituted by one or more, preferably one to four, particularly one or two, substituents selected from C
1-4
alkyl, e.g. methyl or ethyl, C
1-4
alkoxy, e.g. methoxy or ethoxy, halogen, e.g. fluorine, chlorine or bromine, or trifluoromethyl. Ar
2
is preferably an unsubstituted indanyl group.
Preferably, X represents S(O)
n
wherein n is 0, 1 or 2, C≡C, (CH
2
)
2
or CH
2
CH═CH. Particularly advantageous compounds of formula (I) are those in which X represents S(O)
n
wherein n is 0, 1 or 2.
When p is 1, A preferably represents C
1-4
alkylene, more preferably CH
2
, (CH
2
)
2
or (CH
2
)
3
.
Each of groups R
1
, R
2
, R
11
, R
12
, R
15
, R
16
, R
17
, R
18
and R
21
preferably represents H or a C
1-4
alkyl group. R
1
is most preferably a cyclic or branched C
3-4
alkyl group, e.g., a 1-methylethyl or 2-methylpropyl group, and R
2
is most preferably a methyl group.
Each of groups R
13
and R
14
preferably represents H, C
1-3
alkyl or phenyl, which latter group may be substituted by one or more, e.g. one to four, substituents selected from C
1-4
alkyl, e.g., methyl or ethyl, C
1-4
alkoxy, e.g., methoxy or ethoxy, halogen, e.g. fluorine, chlorine or bromine, or CO
2
R
21
.
More preferably, each of groups R
13
and R
14
represents H, C
1-3
alkyl or phenyl, which latter group may be substituted by one or two substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halogen, or CO
2
R
21
.
Most preferably, each of groups R
13
and R
14
represents H, C
1-3
alkyl or phenyl, especially H.
The group Y may represent an optionally substituted aryl or heteroaryl group. Preferably p is 0 when Y represents an optionally substituted aryl or heteroaryl group. Examples of aryl and heteroaryl groups include phenyl, furyl, imidazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl and thienyl groups. The groups phenyl, 2-pyridyl, 4-pyridyl and 5-tetrazolyl are most preferred. Examples of substituents that may be present in the aryl or heteroaryl group include C
1-4
alkyl, e.g. methyl or ethyl, C
1-4
alkoxy, e.g. methoxy or ethoxy, halogen, e.g. fluorine, chlorine or bromine, hydroxyl and trifluoromethyl. One or more, e.g. 1, 2, 3 or 4, substituent groups may be present but preferably only one substituent group is present.
A preferred subset of compounds of formula (I) is one in which W represents —CH
2
— or a bond; Q represents Ar
1
or Ar
2
; in the case where W represents —CH
2
—, Q represents an aryl group Ar
1
wherein Ar
1
represents naphthyl or phenyl; in the case where W represents a bond, Q represents an aryl group Ar
2
wherein Ar
2
represents indanyl; wherein the ring systems which Ar
1
and Ar
2
represent may all be optionally substituted by one or more, e.g. one, two, three or four, substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halogen, or trifluoromethyl; R
10
represents X—(A)
p
—Y; X represents S(O)
n
, C≡C, (CH
2
)
2
or CH
2
CH═CH; n represents 0, 1 or 2; A represents C
1-6
alkylene; p is 0 or 1; Y represents CN, OR
11
, CO
2
R
12
, CON

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